Prostate cancer is the second leading cause of cancer-related death in males in the United States and Europe. One cause of the grave morbidity and mortality related to this malignancy is the development of hormone resistant metastatic bone metastases. Indeed, bone is among the most common sites of metastases for many other common cancers, including lung, breast, and prostate cancer, as well as myeloma and lymphoma. The clinical sequelae of skeletal involvement by tumor metastases includes such complications as pathological fractures, spinal cord compression, hypercalcemia, as well as intractable pain believed to be caused by pressure from the expanding tumor mass, the release of cytokines and the spontaneous formation of small fractures in the metastatic bone. Bone metastasis invariably carries a grim prognosis for the cancer patient, as cure is no longer considered clinically achievable and treatment is limited to palliation in order to make the terminal patient more comfortable.
Because of the lack of therapeutic treatments for patients whose cancers have metastasized, intensive investigation has begun to focus on immunological or vaccination approaches to therapy. One of the problems encountered with vaccination approaches to human malignancy, however, is the mechanism of central and peripheral tolerance that limits the repertoire of self-reactive T cells to those of low avidity to prevent autoimmunity, making it difficult to elicit T cell responses that result in the attack of tumor cells. A primary goal of cancer immunotherapy, therefore, is the breaking of anergy and tolerance with concomitant activation and differentiation of tumor-reactive T cells. Because the balance between immunity and tolerance is in large part regulated at the immunologic interface between T cells and specialized cells that present antigens to T cells, such antigen-presenting cells, particularly dendritic cells, represent important targets for cancer immunotherapy.
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) strategically located in tissues where they efficiently capture and process antigens. DCs mature in response to exposure to pathogens or inflammatory mediators upon which they begin to express molecules which promote not only the migration of DCs to T cell zones of secondary lymphoid organs, but also upregulate the expression of major histocompatibility complex (MHC), and of several costimulatory and adhesion molecules. Upregulation of these factors permits the formation of a synapse between mature DCs and naive T cells which leads to the stimulation and maturation of T cells specific for antigens presented by DCs with which they have come into contact. Because of their role in stimulating and activating T cells, the loading of DCs with antigens in the form of proteins, peptides or RNA/DNA encoding tumor-associated antigens is an important element in the development of vaccines for overcoming tolerance to self-antigens.
The design of immunotherapeutic approaches to cancer also requires the identification of target antigens against which an effective immune response may be stimulated. While a number of tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs) have been identified for certain types of tumors, the delivery and presentation of a tumor-associated or tumor-specific self-antigen in a form that is effective to induce T cell responses remains a major challenge. Cytotoxic T lymphocytes (CTLs) recognize protein antigens as small peptide products of cytoplasmic proteolysis bound to major histocompatibility complex I (MHC I) molecules, while helper T cells recognize peptides of variable sizes complexed to MHC II. Epitope peptide binding to specific class I or II human leukocyte antigen (HLA) isotypes is determined by consensus motifs present in the amino acid sequences of the antigen peptides. Because the quality and duration of T cell receptor signaling at the synapse between DC and T cell influences T cell activation, the ability of a peptide antigen to elicit responses will be related to its affinity for the MHC molecule, determined by the presence of favored amino acids at anchor positions involved in MHC binding and by the presence of amino acids involved in the recognition of the MHC-peptide complex by the T cell receptor. Thus, the identification, delivery and presentation of a tumor-associated antigen in a form effective to elicit tumor- and metastasis-specific T cell responses presents a significant advance in the clinical immunotherapy of malignancy.